Disposable patient interface for intraductal fluid aspiration system

ABSTRACT

Disclosed is a disposable patient interface for an intraductal fluid aspiration system. The interface has a flexible tubular distal member for contacting the patient, and a rigid proximal member forming a vacuum chamber therein. The rigid member has a vacuum aperture for communication with a source of vacuum. The flexible member preferably has a low modulus of elasticity and a high tear strength, such that it can be stretched to fit over a rigid support without rupture.

[0001] This is a continuation-in-part of U.S. patent application Ser.No. 09/870,402, filed May 30, 2001, which is incorporated in itsentirety herein by reference.

[0002] The present invention relates to methods and devices forconducting noninvasive screening assays for indicia of breast cancer orother breast disease.

BACKGROUND OF THE INVENTION

[0003] Breast cancer is by far the most common form of cancer in women,and is the second leading cause of cancer death in humans. Despite manyrecent advances in diagnosing and treating breast cancer, the prevalenceof this disease has been steadily rising at a rate of about 1% per yearsince 1940. Today, the likelihood that a woman living in North Americawill develop breast cancer during her lifetime is one in eight. Thecurrent widespread use of mammography has resulted in improved detectionof breast cancer. Nonetheless, the death rate due to breast cancer hasremained unchanged at about 27 deaths per 100,000 women. All too often,breast cancer is discovered at a stage that is too far advanced, whentherapeutic options and survival rates are severely limited.Accordingly, more sensitive and reliable methods are needed to detectsmall (less than 2 cm diameter), early stage, in situ carcinomas of thebreast. Such methods should significantly improve breast cancersurvival, as suggested by the successful employment of Papinicolousmears for early detection and treatment of cervical cancer.

[0004] In addition to the problem of early detection, there remainserious problems in distinguishing between malignant and benign breastdisease, in staging known breast cancers, and in differentiating betweendifferent types of breast cancers (e.g. estrogen dependent versusnon-estrogen dependent tumors). Recent efforts to develop improvedmethods for breast cancer detection, staging and classification havefocused on a promising array of so-called cancer “markers.” Cancermarkers are typically proteins that are uniquely expressed (e.g. as acell surface or secreted protein) by cancerous cells, or are expressedat measurably increased or decreased levels by cancerous cells comparedto normal cells. Other cancer markers can include specific DNA or RNAsequences marking deleterious genetic changes or alterations in thepatterns or levels of gene expression associated with particular formsof cancer.

[0005] A large number and variety of breast cancer markers have beenidentified to date, and many of these have been shown to have importantvalue for determining prognostic and/or treatment-related variables.Prognostic variables are those variables that serve to predict diseaseoutcome, such as the likelihood or timing of relapse or survival.Treatment-related variables predict the likelihood of success or failureof a given therapeutic plan. Certain breast cancer markers clearly serveboth functions. For example, estrogen receptor levels are predictive ofrelapse and survival for breast cancer patients, independent oftreatment, and are also predictive of responsiveness to endocrinetherapy. Pertschuk et al., Cancer 66: 1663-1670, 1990; Parl and Posey,Hum. Pathol. 19: 960-966, 1988; Kinsel et al., Cancer Res. 49:1052-1056, 1989; Anderson and Poulson Cancer 65: 1901-1908, 1989.

[0006] The utility of specific breast cancer markers for screening anddiagnosis, staging and classification, monitoring and/or therapypurposes depends on the nature and activity of the marker in question.For general reviews of breast cancer markers, see Porter-Jordan et al.,Hematol. Oncol. Clin. North Amer. 8: 73-100, 1994; and Greiner,Pharmaceutical Tech., May, 1993, pp. 28-44. As reflected in thesereviews, a primary focus for developing breast cancer markers hascentered on the overlapping areas of tumorigenesis, tumor growth andcancer invasion. Tumorigenesis and tumor growth can be assessed using avariety of cell proliferation markers (for example Ki67, cyclin D1 andproliferating cell nuclear antigen (PCNA)), some of which may beimportant oncogenes as well. Tumor growth can also be evaluated using avariety of growth factor and hormone markers (for example estrogen,epidermal growth factor (EGF), erbB-2, transforming growth factor(TGF).alpha.), which may be overexpressed, underexpressed or exhibitaltered activity in cancer cells. By the same token, receptors ofautocrine or exocrine growth factors and hormones (for example insulingrowth factor (IGF) receptors, and EGF receptor) may also exhibitchanges in expression or activity associated with tumor growth. Lastly,tumor growth is supported by angiogenesis involving the elaboration andgrowth of new blood vessels and the concomitant expression of angiogenicfactors that can serve as markers for tumorigenesis and tumor growth.

[0007] In addition to tumorigenic, proliferation and growth markers, anumber of markers have been identified that can serve as indicators ofinvasiveness and/or metastatic potential in a population of cancercells. These markers generally reflect altered interactions betweencancer cells and their surrounding microenvironment. For example, whencancer cells invade or metastasize, detectable changes may occur in theexpression or activity of cell adhesion or motility factors, examples ofwhich include the cancer markers Cathepsin D, plasminogen activators,collagenases and other factors. In addition, decreased expression oroverexpression of several putative tumor “suppressor” genes (for examplenm23, p53 and rb) has been directly associated with increased metastaticpotential or deregulation of growth predictive of poor disease outcome.

[0008] Thus, the evaluation of proliferation markers, oncogenes, growthfactors and growth factor receptors, angiogenic factors, proteases,adhesion factors and tumor suppressor genes, among other cancer markers,can provide important information concerning the risk, presence, statusor future behavior of cancer in a patient. Determining the presence orlevel of expression or activity of one or more of these cancer markerscan aid in the differential diagnosis of patients with uncertainclinical abnormalities, for example by distinguishing malignant frombenign abnormalities. Furthermore, in patients presenting withestablished malignancy, cancer markers can be useful to predict the riskof future relapse, or the likelihood of response in a particular patientto a selected therapeutic course. Even more specific information can beobtained by analyzing highly specific cancer markers, or combinations ofmarkers, which may predict responsiveness of a patient to specific drugsor treatment options.

[0009] Methods for detecting and measuring cancer markers have beenrevolutionized by the development of immunological assays, particularlyby assays that utilize monoclonal antibody technology. Previously, manycancer markers could only be detected or measured using conventionalbiochemical assay methods, which generally require large test samplesand are therefore unsuitable in most clinical applications. In contrast,modem immunoassay techniques can detect and measure cancer markers inrelatively much smaller samples, particularly when monoclonal antibodiesthat specifically recognize a targeted marker protein are used.Accordingly, it is now routine to assay for the presence or absence,level, or activity of selected cancer markers by immunohistochemicallystaining breast tissue specimens obtained via conventional biopsymethods. Because of the highly sensitive nature of immunohistochemicalstaining, these methods have also been successfully employed to detectand measure cancer markers in smaller, needle biopsy specimens whichrequire less invasive sample gathering procedures compared toconventional biopsy specimens. In addition, other immunological methodshave been developed and are now well known in the art which allow fordetection and measurement of cancer markers in non-cellular samples suchas serum and other biological fluids from patients. The use of thesealternative sample sources substantially reduces the morbidity and costsof assays compared to procedures employing conventional biopsy samples,which allows for application of cancer marker assays in early screeningand low risk monitoring programs where invasive biopsy procedures arenot indicated.

[0010] For the purpose of breast cancer evaluation, the use ofconventional or needle biopsy samples for cancer marker assays is oftenundesirable, because a primary goal of such assays is to detect thecancer before it progresses to a palpable or mammographically detectabletumor stage. Prior to this stage, biopsies are generallycontraindicated, making early screening and low risk monitoringprocedures employing such samples untenable. Therefore, there is generalneed in the art to obtain samples for breast cancer marker assays byless invasive means than biopsy.

[0011] Thus, serum withdrawal has been attempted for breast cancermarker assays. Efforts to utilize serum samples for breast cancer markerassays have met with limited success. The targeted markers are eithernot detectable in serum, or telltale changes in the levels or activityof the markers cannot be monitored in serum. In addition, the presenceof breast cancer markers in serum may occur at the time ofmicro-metastasis, making serum assays less useful for detectingpre-metastatic disease. In contrast, fluid within the mammary glandsthemselves is expected to contain much higher and more biologicallyrelevant levels of breast cancer markers than serum, particularly inview of the fact that 80%-90% of all breast cancers occur within theintraductal epithelium of these glands. Fluid within the breast ducts isexpected to contain an assemblage and concentration of hormones, growthfactors and other potential markers comparable to those secreted by, oracting upon, the surrounding cells of the alveolar-ductal system.Likewise, mammary fluid is expected to contain cells and solid cellulardebris or products that can be used in cytological or immunologicalassays to evaluate intracellular or cell surface markers that may not bedetectable in the liquid fraction of mammary fluid.

[0012] Previous attempts to develop non-invasive breast cancer markerassays utilizing mammary fluid samples have included studies of mammaryfluid obtained from patients presenting with spontaneous nippledischarge. In one of these studies, conducted by Inaji et al., Cancer60: 3008-3013, 1987, levels of the breast cancer marker carcinoembryonicantigen (CEA) were measured using conventional, enzyme linkedimmunoassay (ELISA) and sandwich-type, monoclonal immunoassay methods.These methods successfully and reproducibly demonstrated that CEA levelsin spontaneously discharged mammary fluid provide a sensitive indicatorof nonpalpable breast cancer. In a subsequent study, also by Inaji etal., Jpn. J. Clin. Oncol. 19: 373-379, 1989, these results were expandedusing a more sensitive, dry chemistry, dot-immunobinding assay for CEAdetermination. This latter study reported that elevated CEA levelsoccurred in 43% of patients tested with palpable breast tumors, and in73% of patients tested with nonpalpable breast tumors. CEA levels in thedischarged mammary fluid were highly correlated with intratumoral CEAlevels, indicating that the level of CEA expression by breast cancercells is closely reflected in the mammary fluid CEA content. Based onthese results, the authors concluded that immunoassays for CEA inspontaneously discharged mammary fluid are useful for screeningnonpalpable breast cancer.

[0013] Although the evaluation of mammary fluid has been shown to be auseful method for screening nonpalpable breast cancer in women whoexperience spontaneous nipple discharge, the rarity of this conditionrenders the methods of Inaji et al, inapplicable to the majority ofwomen who are candidates for early breast cancer screening. In addition,the first Inaji report cited above determined that certain patientssuffering spontaneous nipple discharge secrete less than 10 μl ofmammary fluid, which is a critically low level for the ELISA andsandwich immunoassays employed in that study. It is likely that otherantibodies used to assay other cancer markers may exhibit even lowersensitivity than the anti-CEA antibodies used by Inaji and coworkers,and may therefore not be adaptable or sensitive enough to be employedeven in dry chemical immunoassays of small samples of spontaneouslydischarged mammary fluid.

[0014] In view of the above, an important need remains in the art formore widely applicable, non-invasive methods and devices for obtainingbiological samples for use in evaluating, diagnosing and managing breastdisease including cancer, particularly for screening early stage,nonpalpable breast tumors. Biological samples thus obtained can be usedto evaluate, diagnose and manage breast disease, particularly bydetecting or measuring selected breast cancer markers, or panels ofbreast cancer markers, to provide highly specific, cancer prognosticand/or treatment-related information, and to diagnose and managepre-cancerous conditions, cancer susceptibility, breast infections andother breast diseases.

SUMMARY OF THE INVENTION

[0015] Disclosed is a disposable patient interface for use with anintraductal fluid aspiration device. More specifically, the interfacecomprises a flexible tubular membrane attached to a rigid cap at itsproximal end. The cap contains a vacuum port for connection to a sourceof vacuum.

[0016] Preferably, the tubular membrane has an open end having anunstressed diameter within the range of about 2 inches to about 4inches. Preferably, the opposite end of the tubular membrane has anunstressed diameter no more than about 4 inches. The tubular membrane isformed of a material exhibiting a high tear strength such that themembrane can be stretched up to 150%, or up to 200%, or more of itsinitial diameter without tearing. The tubular membrane has an unstressedaxial length within the range of from about 1 inch to about 6 inches,and more preferably, within the range of from about 2 inches to about 4inches.

[0017] In one embodiment, the tubular membrane is formed of a styreneblock copolymer sold under the tradename KRATON™, and has a wallthickness no more than about 0.05 inches, and for some materials, nomore than about 0.015 inches. The proximal cap may form an interiorchamber and is preferably formed of a material exhibiting sufficientrigidity to resist collapse when experiencing a vacuum of at least about150 mm Hg, and more preferably, resists collapse at 250 mm Hg or more.

[0018] The proximal cap may further be configured with a first retentionstructure to cooperate with a corresponding retention structure on ahandpiece, thereby resulting in a releasable connection therewith. Theretention structure may be in the form of a recess on either the cap orhandpiece and a corresponding protrusion on the opposite piece forfitting with the recess. It may also be in the form of a rigidprojection on the handpiece that impinges upon a smooth surface of thecap thereby interfering with its subsequent relative movement.

[0019] According to another aspect of the present invention, a methodfor making a disposable patient interface comprises the steps of moldingthe proximal cap and overmolding the flexible patient interface.

[0020] Further features and advantages of the present invention willbecome apparent to those of skill in the art in view of the detaileddescription of preferred embodiments which follows, when consideredtogether with the attached drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021]FIG. 1 is a schematic illustration of a portable, self-containedintraductal fluid aspiration device.

[0022]FIG. 2 is an illustration of a portable self-contained intraductalfluid aspiration device as in FIG. 1, schematically illustrating aplurality of annular compression rings.

[0023]FIG. 3 is a schematic illustration of a desktop or cart topembodiment of an intraductal fluid aspiration device in accordance withthe present invention.

[0024]FIG. 4 is a schematic illustration of a sample collection patch,in communication with the flow path between the patient and a vacuumsource.

[0025]FIG. 5 is an isometric illustration of another embodiment of anintraductal fluid aspiration power head.

[0026]FIG. 6 is an illustration of an intraductal fluid aspiration powerhead as in FIG. 5, from a rear isometric view.

[0027]FIG. 7 is an exploded view illustration of the components of anintraductal fluid aspiration power head.

[0028]FIG. 8 is a cross-sectional view taken along the line 8-8 of FIG.5.

[0029]FIG. 9 is an illustration of one embodiment of an inflatablebladder for use with an intraductal fluid aspiration power head.

[0030]FIG. 10a is an illustration of a release mechanism for use inconjunction with an intraductal fluid aspiration power head.

[0031]FIG. 10b is an illustration of a release mechanism in a disengagedposition.

[0032]FIG. 11 is an illustration of one embodiment of a patientinterface for use with an intraductal fluid aspiration power head.

[0033]FIG. 12 is an illustration of one embodiment of a self-containedintraductal fluid aspiration device.

[0034]FIGS. 13A and 13B illustrate the petal range of motiondemonstrating an initial starting position and a rough adjustedposition.

[0035]FIGS. 14A and 14B illustrate the varying diameter of the patientinterface between a deflated and inflated state of the inflatablebladder of FIG. 9.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0036] Referring to FIG. 1, there is illustrated a schematicrepresentation of a portable, self-contained intraductal fluidaspiration device 20 in accordance with one aspect of the presentinvention. The aspiration device 20 includes a housing 22, forcontaining various controls and functional components of the device 20.One or more controls and/or indicators 25 may be provided on thehousing, for controlling various aspects of the device such as suction,compression, and other features (e.g., heat, ultrasound) which may beincluded depending upon the intended functionality of the aspirationdevice 20. The housing 22 may be formed by extrusion, injection moldingor other well known techniques from a suitable biocompatible materialsuch as high density polyethylene, nylon, polyethylene terephthalate, orothers well known in the art. The housing is preferably formed in anergonomic configuration, to comfortably facilitate grasping in one handduring use.

[0037] The housing 22 is provided with a patient or breast interface 24,which may either be permanently attached to the housing 22 or removablyattached such as for cleaning or disposal. Breast interface 24 has aproximal end 26, a distal end 28, and a body 30 extending therebetween.The interface 24 has a tissue contacting surface 32 defining a firstconcavity 34 for receiving a breast and a second concavity 38 forreceiving a nipple. The tissue contacting surface 32 may be an integralsurface on the body 30, or may comprise a separate interior liner whichis adhered to or otherwise fit within and/or secured to the body 30.

[0038] The body 30 may be manufactured in any of a variety of ways, suchas injection molding, blow molding tube stock within a tapered capturetube, or other known manners, using any of a variety of well knownbiocompatible polymeric materials. Preferably, the body 30 istransparent, which may be achieved by forming from polycarbonate, orother relatively clear materials known in the art. In one embodiment,the generally frusto-conical body 30 is sufficiently rigid to providesupport for a flexible interior liner.

[0039] The dimensions of the interface 24 may be varied widely, as willbe appreciated by those of skill in the art in view of the disclosureherein. In general, the distal end 28 of the flexible body 30 isprovided with an elastic sealing ring 35 having an inside diameterwithin the range of from about 2″ to about 10″. The distal limit of thesecond concavity 38 has an inside diameter within the range of fromabout 1″ to about 4″. The first concavity 34 has an axial length fromproximal end 26 to distal end 28 within the range of from about 0″ toabout 12″, and, in many embodiments, within the range of from about 2″to about 6″. The first concavity 34 has a generally conical or bellshaped interior configuration, as will be appreciated by those of skillin the art.

[0040] Preferably, the breast interface 24 is provided with a dynamiccompression zone 42, having one or more compression elements 45 forcompression in the mid breast region to facilitate intraductal fluidaspiration. Although the specific dimensions will vary from patient topatient, as well as with age and parity, the breast includes a pluralityof ducts which are generally confluent in the direction of a pluralityof external openings on the nipple. Most of the intraductal volume iscontained in the distal one-half or one-third of the breast (from thepatient's perspective). Thus, the inventors presently believe that acompression zone approximately centered around the midbreast region inan average patient and extending anatomically distally will optimizefluid transport in the duct.

[0041] Referring to FIG. 2, the dynamic compression zone 42 isschematically illustrated (not to scale) as comprising a plurality ofannular compression rings 44, 46, 48 and 50. Preferably, the annularcompression rings are in operative communication with a driver 52 in thehousing 22, to permit sequential operation. One operation mode mimics aperistaltic motion such that tissue compression is accomplishedsequentially proximally with respect to the device starting withcompression ring 44 followed by compression ring 46 followed bycompression ring 48 followed by compression ring 50. As will be apparentto those of skill in the art in view of the disclosure herein, any of awide variety of compression ring numbers and configurations may beutilized in accordance with the present invention. Thus, theillustration of four compression rings in FIG. 2 is not consideredlimiting on the scope of the invention. In general, anywhere from aboutone to about twenty compression elements 45 may be utilized, in ringform or nonannular form, and, preferably, between about three and tenare contemplated in most embodiments.

[0042] The compression elements 45 may comprise any of a variety ofstructures, such as inflatable tubular elements or other inflatablestructures, or mechanical compression elements such as rollers. In theillustrated embodiment, which is not drawn to scale in order to improveclarity, the dynamic compression zone 42 comprises a plurality ofannular, inflatable, tubular compression rings each of which isconnected to the driver 52 by a unique conduit 56. The driver 52preferably includes a microprocessor or other central processing unitfor sequentially driving the compression elements 45 as describedpreviously. In one embodiment, the driver 52 includes a pump forcontrollably inflating and deflating each compression ring in responseto the microprocessor and in accordance with the predeterminedcompression protocol. Inflation media such as air, water, or gel may beutilized, depending upon the desired performance characteristics. In oneembodiment, a heat retaining gel such as morphing gel, available fromDow Corning, is utilized to enable the delivery of heat during thecompression cycle.

[0043] The compression elements 45 may alternatively be connected toeach other by a capillary tube or flow restriction orifice, or pressurerelief valves to enable compression (inflation) in a predeterminedsequence. Alternatively, the compression elements 45 may be in fluidcommunication with each other, with each having a wall with a uniquedurometer or elasticity such that each element inflates as a uniquethreshold inflation pressure is reached and/or exceeded.

[0044] The microprocessor may be programmed to a particular pumping andcompression cycle characteristic, or may be adjustable by the user tooptimize the aspiration function as desired. For example, compressioncycles may be peristaltic, with a sequential compression pattern fromchest wall (distal end 28) to the proximal end 26. Alternatively, thecompression cycle may be non peristaltic pulsatile. Vacuum may beapplied constantly throughout the pumping cycle, or may be pulsatileeither in phase or out of phase with the compression cycles.

[0045] The aspiration device 20 is further provided with a vacuumgenerator such as a pump in the housing 22, in communication with thesecond concavity 38 by way of a vacuum conduit (not shown). Associatedelectronics, such as a power source and driving circuitry are preferablyconnected to a control 25 to enable the user to selectively activate anddeactivate the vacuum. Alternatively, the pump and vacuum functions maybe fully automatic, and pre-programmed into the micro-processor. Thepump is generally capable of generating a vacuum within an operatingrange of from 0 (pump off) to about 300 mm/Hg. Although vacuum in excessof 300 mm/Hg may also be utilized, vacuum in this area or higher maycause rupture of microvasculature and is unnecessary to accomplish theobjectives of the present invention. For this reason, limit valves maybe provided in communication with the vacuum conduit, as are known inthe art, to limit the vacuum to no more than about 200 mm Hg, or 250 mmHg, or 300 mm Hg. Within the methods of the invention, negativepressures of 50-200 mm Hg are preferred, and these pressures aremaintained, preferably intermittently, for approximately 1-15 minutes,depending on the sensitivity of individual patients, oxytocin dosage andother factors.

[0046] The foregoing embodiment is useful in a variety of settings,particularly for in-home intraductal aspiration. In an alternativeembodiment of the present invention, a desk top, or mobile cart top,unit 60 is provided, such as for the physician's office or otherconventional clinical setting. See FIG. 3. The desk top intraductalfluid aspiration system 60 comprises a control unit 62, in communicationwith one or more power heads 64 by way of an elongate flexible controlline 66. The power head 64 is provided with a disposable user interface68 which may be similar or identical to the interface 24 describedpreviously. In this embodiment, the interface 68 is preferably removablyconnected to the power head 64, to facilitate one time use andsubsequent disposal of the interface 68. Alternatively, the entireinterface and power head assembly may be one time use disposable.

[0047] The control 62 preferably includes the vacuum pump, and otherdriver circuitry and controls as may be needed depending upon theintended functionality of the desk top unit 60. For example, a vacuumpump (not illustrated) is in communication with the disposable userinterface 68 by way of a vacuum lumen (not illustrated) extendingthroughout the length of the control line 66. Additional lumens orwiring extend through the control line 66 for accomplishing theperistaltic or other sequential compression motion of the dynamiccompression zone 42 as has been discussed.

[0048] In either a diagnostic or non-diagnostic embodiment, a samplecollector or reservoir may be positioned in fluid communication with thedisposable user interface 68, to allow collection of intraductal fluid.The sample collector or container may be removable, such as to enabletransport of collected intraductal fluid to a diagnostic laboratory orother facility for diagnostic analysis.

[0049] Preferably, the disposable user interface 68 is provided with aheat source, such as a heat retaining gel or other media for surroundingor contacting the interface 24, and/or for inflating the compressionelements as has been previously discussed. Alternatively, resistanceheating elements may be provided in the disposable user interface 68 orassociated power head 64, powered by way of electrical conductorsextending throughout the control line 66. In an embodiment where thedynamic compression zone 42 includes elements filled with a heatretaining gel or other media for retaining heat, the breast interface 24may be removed and heated such as in a microwave oven or other heatsource prior to use. An ultrasound source may also be provided in thecontrol unit 62 or power head 64, for driving one or more ultrasoundtransducers in the power head 64 to assist in initial removal of keratinplugs that may occur at the opening of the ducts, and possibly also toserve as a heating source. Alternatively, a heating fluid may becirculated through a closed loop such as from a heater in the controlunit 62, through a first lumen in control line 66 to a heat exchanger inthe power head 64 or patient interface, and back through a second lumenin control line 66 to the control unit 62.

[0050] The volume of expressed mammary fluid will vary depending on avariety of factors, including patient sensitivity to oxytocin, if used,dosage of oxytocin delivered, time and pressure and other variables ofbreast pump administration, and other factors. For certain relativelylow sensitivity breast marker assays, a volume of expressed mammaryfluid of 300-500 μl is preferred to provide ample material forconducting the assay, and these volumes are expected to be obtainablefrom a substantial proportion of women treated according to the abovemethods. To express 300-500 μl of mammary fluid, some women will requirerepeated stimulation treatments, perhaps requiring pooling of mammaryfluid samples obtained during multiple patient visits. However, for moresensitive assays of the invention, e.g. solid phase immunoassays, muchsmaller samples of 3 μl or less may be sufficient to carry out theassays. This is particularly so in the case of breast cancer markersthat are naturally secreted into the mammary fluid and are thereforeexpected to be present in very high concentrations compared to, forexample, breast epithelial cell surface antigens or intracellularantigens that may not be secreted.

[0051] Although one aspect of the present invention lies in the novel,non-invasive methods for obtaining biological samples from mammaryfluid, an additional aspect of the invention involves the use of thecollected sample for detecting and/or measuring important breast diseasemarkers. The invention thus enables the convenient application of abroad range of assay methods incorporating known procedures and reagentsfor determining the presence and/or expression levels of breast diseasemarkers, particularly breast cancer markers, in biological samples.

[0052] During or after the mammary fluid expression step, a biologicalsample is collected from the expressed mammary fluid. A range ofsuitable biological samples are contemplated and will be useful withinthe methods of the invention, including whole mammary fluid, selectedliquid or solid fractions of the mammary fluid, whole cells or cellularconstituents, proteins, glycoproteins, peptides, nucleotides (includingDNA and RNA polynucleotides) and other like biochemical and molecularconstituents of the mammary fluid.

[0053] Sample collection can be achieved simply by receiving theexpressed mammary fluid within a suitable reservoir such as within or incommunication with the concavity 38 with or without an absorptive samplecollection media. Samples can be collected directly on to orsubsequently exposed to conventional buffers, diluents, extraction orchromatographic media, filters, etc., to stabilize or prepare the samplefor further processing or direct incorporation into a desired assay. Incertain embodiments of the invention, the expressed mammary fluid iscollected directly onto a solid phase medium, such as a microscopicglass slide, nitrocellulose filter, affinity column, dot blot matrix,cotton swab, or other like medium, that will selectively adsorb, bind,filter or otherwise process desired components of the mammary fluid,such as bulk or selected proteins, for convenient incorporation into adesired assay.

[0054] Alternatively, the sample may be collected from the patient'sskin using any of the collection devices disclosed herein, followingremoval of the patient interface. The relatively high viscosity of theNAF sample tends to allow the sample to adhere to the patient's skinwhere it can be conveniently collected.

[0055] Referring to FIG. 4, a flow path such as lumen 39 draws collectedfluid from the patient through a sample collection patch 41. The samplecollection patch 41 may be positioned directly against the externalopening of the ducts, to minimize fluid loss in the device.

[0056] In the illustrated embodiment, the sample collection patch 41 ismoveably positioned within the flow path, with a mild biasing force inthe distal direction. In this manner, the patch 41 can maintain lowpressure contact with the distal surface of the nipple throughout arange of axial positions along the longitudinal axis of the patientinterface. Preferably, an axial range of motion is provided for at leastthe tissue contacting portion of the patch 41 of at least about 0.25inches. In some embodiments, the range of from about 0.5 inches to about2 inches or more may be accomplished. In the illustrated embodiment, theaxial motion of the sample collection patch 41 is achieved by allowingbending or pivoting of the patch 41, throughout the patch and/or at areleasable attachment point 43 to either the patient interface 24 or thehousing 22. Axial movement of the sample collection patch mayalternatively be accomplished by mounting the sample collection patch onthe surface of a compressible foam, which will compress in response topressure from the patient. Alternatively, the compressible foam may formthe sample collection media, without a separate patch, as is describedbelow.

[0057] The sample collection patch 41 or other sample collection mediamay be removably attached to the aspiration device 20 such as by one ormore releasable connections 47, which may comprise adhesive surfaces ormechanical interfit surfaces such as an annular recess for receiving thepatch 41, radially inwardly extending tabs for receiving the patch 41,or others as will be apparent to those of skill in the art in view ofthe disclosure herein. The patch 41 may consist entirely of a flexibleabsorptive medium. Alternatively, the patch may include an absorptivemedium in combination with a support structure such as a backing plate,or an annular ring for surrounding the patch 41, and facilitatingreleasable connection to the aspiration device 20.

[0058] The patch 41 is preferably removable from the aspiration device20. The patch 41 may be removed through the first concavity or chamber34, by hand or using tweezers, hemostats or other retrieval device.Alternatively, the patch 41 may be removed through a lateral opening 49in the side wall of the aspiration device 20. As a further alternative,the patch 41 may be removed following disconnection of the patientinterface 24 from the housing 22.

[0059] The patch 41 or distal surface of a solid sample collectionmedium such as a foam may have any of a variety of configurations,depending upon other aspects of the device design. In the illustratedembodiment, the patch 41 is a generally planar membrane. Alternatively,the patch 41 or patient contacting surface of a solid foam or othercollection device may be conical or otherwise concave in the directionof the patient. The sample collection patch 41 or other samplecollection structure may also have a component which extends distallytowards the patient, from a lower portion of the patch 41, to captureany sample which may drop under the influence of gravity without firstbeing absorbed by the patch 41.

[0060] The fluid capacity of the patch 41 or other collection media maybe varied, depending upon the intended patient population and purpose ofthe aspiration. In general, sample sizes in the microliter or lowmilliliter range may be useful for different types of assays. For acertain patient populations, the volume of fluid expressed may reach inexcess of 1 to 5 milliliters or greater, in which case a fluidcollection chamber may be provided on the device in the area of theillustrated opening 49 on FIG. 4. Any of a variety of such variationswill be apparent to those of skill in the art in view of the disclosureherein, taking into account the purpose of the aspiration.

[0061] The composition and construction of sample collection patch 41will vary, depending upon the nature of the intended assay. For example,any of a wide variety of porous or absorptive materials may be utilizedto collect cellular and cellular component samples which may be used forcytological exam. Materials such as conventional filter paper, cottongauze, fiber webs such as knitted fabrics or nonwoven rayon or cellulosefibers may be used. A variety of microporous films comprising materialssuch as nylon 66, polycarbonate, modified polyvinyl fluoride andpolyether sulfone may alternatively be used. Embodiments of thecollection patch 41 which are intended to permit chemical or biochemicalassays may additionally be provided with any of a variety of binders foreither chemically binding with an analyte or adsorbing the analyte to bedetermined. The binder layer may additionally include a specific bindingpartner of the analyte to be determined, such as a polyclonal ormonoclonal antibody or an antigen matched to a specific antibody desiredto be measured in the extracted fluid. Other binding systems which arematched to the desired analyte or analytes may be readily adapted foruse in the present invention, as will be understood by those of skill inthe art. The range of contemplated sample collection procedures andmaterials that are useful within the invention is broad, and selectedmethods and materials will vary with each selected assay, as will beunderstood and readily practiced by those skilled in the art.

[0062] The sample collection patch may be constructed of any suitablematerial. In preferred embodiments, the sample collection patch includesa membrane or filtration medium upon, through, or in which a fluidsample is collected. The sample collection patch may be of any suitableshape. While circular or square patches are preferred for manyapplications, other shapes may also be used. The sample collection patchshould be of sufficient size such that an adequate sample may becollected.

[0063] The sample collection patch may include a material capable ofproviding depth filtration or sieve filtration of a sample. In depthfiltration, particulates are trapped both within the matrix and on thesurface of the filtration medium. Depth filters are composed of randommats of metallic, polymeric, inorganic, or organic materials. Depthfilters rely on the density and thickness of the mats to trapparticulates and fluids, and generally retain large quantities ofparticulates or fluids within the matrices. Certain disadvantages ofdepth filters include media migration, which is the shifting of thefilter medium under stress, and particulate unloading at highdifferential pressures. Advantages of depth filters include reducedcost, high throughputs, high volume-holding capacity, removal of a rangeof particle sizes, and high flow rates.

[0064] In sieve filtration, particulates larger than the pore size of amembrane are trapped, while smaller particulates pass through themembrane but may be captured within the membrane by some othermechanism. Sieve filtration membranes are generally polymeric filmsapproximately 120 microns thick with a narrow pore size distribution.Certain disadvantages of sieve filtration include lower flow rates andlower particulate holding capacity. Advantages include absolutesubmicron pore size ratings, no channeling or bypass, capacity forretaining bacteria and particles, low extractables, sterilizable, andintegrity testable.

[0065] In various embodiments, the sample collection patch includes oneor more filtration media such as the filtration media manufactured byPall Gelman Sciences of East Hills, N.Y. Such filtration media that maybe suitable for use in particular assays of the various embodimentsinclude filtration media originally developed for use in bloodseparations. Such filtration media may include polyester filtrationmedia such as Pall Gelman's Hemasep™ modified polyester materials,polyether sulfone membranes such as the Presense™ membrane, Cytosep®single layer fiber composite membrane, and Leukosorb® medium. Othersuitable filtration media may include the Predator™ membrane, apolyether sulfone membrane that is surface modified to possess nitrogroups.

[0066] Pall Gelman's Biodyne® nylon 6,6 membranes may also be suitablefor use in sample collection patches for certain assays. UnmodifiedBiodyne® nylon 6,6 membrane may be preferred for some applications.Alternatively, the Biodyne® nylon 6,6 membrane may be surface modifiedwith quaternary ammonium groups so as to impart a positive charge to thepore surfaces, thereby promoting strong ionic bonding of negativelycharged analytes. Likewise, the Biodyne® nylon 6,6 membrane may besurface modified with carboxyl groups so as to impart a negative chargeto the pore surfaces, thereby promoting strong ionic bonding ofpositively charged analytes. Such carboxyl group surface-modifiedBiodyne® nylon 6,6 membranes may be derivatized via coupling reactionsthrough the carboxyl groups at the pore surfaces.

[0067] In various embodiments other membranes may be preferred for usein sample collection patches, such as Biotrace® nitrocellulosemembranes, Fluorotrans® polyvinylidene difluoride (PVDF) membranes,Immunodyne® ABC nylon 6,6 affinity membranes having a high density ofcovalent binding sites capable of permanently immobilizing proteins andpeptides on contact, and Ultrabind™ aldehyde-modified polyether sulfonemembranes capable of providing covalent binding to amine groups onproteins.

[0068] Various absorbent materials also available from Pall Gelman mayalso be used in certain embodiments, such as conjugate pads comprised ofborosilicate glass with no binder or with polyvinylacetate (PVA) oranother suitable binder, Loprosorb™ low protein binding hydrophilicfibrous medium, cellulose absorbent papers, Loprodyne® internallysupported nylon 6,6 membrane with low protein binding, or Z-Bind™post-treated modified polyether sulfone membrane.

[0069] Ion exchange membranes may be preferred for use in samplecollection patches for certain assays. Such membranes may include PallGelman's Raipore™ ion-exchange polytetrafluoroethylene (PTFE) cationicor anionic membranes, and microporous ion exchange membranes constructedof polyether sulfone and possessing either sulfonic acid or quaternaryammonium groups on the membrane surface.

[0070] In various applications, it may be preferred to use a hydrophobicand/or oleophobic material in a sample collection patch. Materialssuitable for use in such applications may include Pall Gelman'sHydrolon® nylon 6,6 membranes, Hydrolon® PTFE membranes, Supor® Rpolyethersulfone membrane, and Pallflex composite materials.

[0071] The above-mentioned filtration media available from Pall Gelmanare representative examples of the wide variety of commerciallyavailable filtration media that may be suitable for use in samplecollection patches. Various filtration media available from othermanufacturers may also be suitable for use in sample collection patches,as may custom-manufactured filtration media. Suitable filtration mediamay include a single material, e.g., a single membrane, or may be acomposite manufactured from two or more materials, e.g., variouscombinations of membranes, woven and nonwoven support materials, wovenand nonwoven filtration media, barrier materials, and other materials.The sample collection patch may further include additional substances,such as reagents, buffers, probes, surfactants, binders, indicators,preservatives, and the like, such as may be useful in performing variousassays.

[0072] Such filtration media may be bonded to a flexible structure,spring or other support to allow movement in and out of the collectionchamber and to also allow ease of removal of the material for samplehandling and removal. Alternatively, a closed-cell foam structure may besubstituted for such media, thereby allowing movement in the chamberwhile maintaining contact with the nipple, either as a stand-alonecollection medium or with a membrane bonded at the surface of themedium. Such media may also act as contamination barriers, protectingthe powerhead circuit and pump system in the control console fromcontamination by body fluids in the negative pressure air path.

[0073] Thus, the present invention provides a method of screeningintraductal breast fluid for one or more breast disease markers. Themethod comprises the steps of contacting the breast with a mechanicalintraductal fluid aspiration device, and activating the device to applycompression and suction to the breast during a period of nonlactation toremove intraductal breast fluid. The fluid is thereafter screened suchas by cytological examination and/or biochemical screening for breastdisease markers. In one embodiment, the method further comprises thestep of applying heat from the device to the breast.

[0074] There is also provided an intraductal breast fluid screeningdevice. The device comprises a tissue contacting surface defining afirst concavity for receiving a breast and a second concavity forreceiving a nipple. A driver for imparting compressive force on at leasta portion of the tissue contacting surface defining the first concavityis additionally provided. A vacuum conduit is provided in communicationwith the second concavity, and a sample collector may be provided incommunication with the second concavity. The sample collector may be areservoir, or an absorptive patch for absorbing or retaining a sample.Preferably, the collection patch is removable from the aspirationdevice.

[0075] The required sample size may vary, depending upon the intendedassay or screening test. For example, relatively larger fluid volumeswill be required for cytological examination as is well understood inthe art. Relatively smaller sample sizes may suffice for monoclonalantibody or other specific binding chemistry assays or biochemicalmarkers.

[0076] Referencing FIG. 5, an alternative embodiment of an intraductalfluid aspiration power head 100, or patient interface unit, inaccordance with one aspect of the present invention is illustrated. Thepower head 100 is preferably formed in an ergonomic configuration tocomfortably facilitate grasping in one hand during use and comprises asupport such as a plurality of adjustable petals 126 that define anadjustable first concavity 164 for receiving a breast. There aregenerally between about two and about twenty petals, preferably, betweenfour and eight petals, and six petals are present in one embodiment. Thepetals 126 are hingedly or otherwise movably connected to the main body(132 of FIG. 7) and are operatively coupled to a slide collar 134 viapinned links 136 or pivots.

[0077] A control is provided, to enable rough sizing of the device toaccommodate a range of patient sizes. In the illustrated embodiment, thecontrol comprises an adjustment ring 140. The slide collar 134 iscarried by the adjustment ring 140, which is threaded onto the main body(132 of FIG. 7). As the adjustment ring 140 is rotated onto the mainbody 134, it translates linearly in a longitudinal direction 168. Theslide collar 134 is in sliding engagement with the adjustment ring 140such that the slide collar 134 does not rotate as the adjustment ring140 is twisted about the main body 132.

[0078] In operation, the adjustment ring 140 is manually rotated aboutthe main body, which causes the slide collar 134 to translate in alinear, longitudinal direction 168, thereby displacing the links 136,which cause the petals to pivot inward or outward about their connectionpoint to the main body.

[0079] The support may take any of a variety of forms, and stillaccomplish the intended functional objective of providing supportagainst which a movable element, such as an inflatable bladder(discussed below), will apply compressive pressure to the breast. Thus,the support may take the form of a rigid conical or hemisphericalstructure, or a flexible structure, such as a woven material orrelatively inelastic polymeric wall. In general, however, the support ispreferably adjustable in size to accommodate any of a wide variety ofpatients.

[0080] The illustrated support is one manner in which adjustability canbe achieved. Alternatively, any of a variety of structures which allowthe inside diameter of the distal opening of the support to be radiallyenlarged or reduced may be utilized. For example, the wall of thesupport may include a helical spring or other element which, when adistal end is rotated or otherwise manipulated relative to a proximalend, a radial reduction or enlargement is achieved. Alternatively, aflexible strap or band, such as a woven fabric, may be wrapped aroundand attached to itself using any of a variety of fasteners, such as hookand loop (e.g., Velcro®), snaps, or other fasteners known in the art.This construction is known in currently available blood pressure cuffs.

[0081] The foregoing structures take into account the usual circumstancethat the range of inflation of the inflatable bladder as discussed belowwill generally be smaller than the range in patient sizes. Thus, thesupport can be rough adjusted so that the patient interface may befitted to the patient with the inflatable bladders deflated, therebyensuring that inflation of the inflatable bladders or other compressionstructure will accomplish a sufficient compression and minimize patientto patient performance variability. Additional details of the inflatablebladders will be discussed below.

[0082] The power head 100 is further provided with a patient interface154, which may either be permanently attached to the power head 100 orremovably attached such as for cleaning or disposal. In at least oneembodiment, as shown in FIG. 11, patient interface 154 is a disposablesheath and includes a flexible frustoconical portion 248, or membrane,made of any of a variety of well known biocompatible polymeric materialssuch as silicone or any of a number of well known styrene blockcopolymers sold under the trade name Kraton, manufactured by KratonPolymers. Examples of suitable materials may include, but are notlimited to, styrene-butadiene-styrene (SBS),styrene-ethylene-butylene-styrene (SEBS), styrene-isoprene-styrene(SIS), or styrene-ethylene-propylene (SEP). Suitable polymers preferablyexhibit a very low modulus of elasticity, allowing the material tostretch several times its original length, and a relatively high tearstrength and optionally transparency, thus allowing an operator to seeinto the device to properly position a breast therein. The polymer ispreferably bondable to polycarbonate or polypropylene, and is glutinouswhen contacted with certain materials thus allowing it to grip thepetals 126 when mounted, while not adhering to latex, thereby allowingan operator wearing latex gloves to easily handle the patient interface154.

[0083] The flexible portion 248 defines the tissue contacting surface156 and is supported by the petals 126 which define the first concavity164. The patient interface 154 is further configured with a relativelyrigid proximal portion 250 configured to fit within the second concavity166. The rigid portion 250 may be sized to receive a nipple, and has aninside diameter within the range of from about 0.5 inches to about 4inches, and in one embodiment, has a length of about 1.5 inches and adiameter at its distal end of about 1.5 inches.

[0084] The rigid portion 250 terminates proximally at a tip 254 whichhas a lumen formed therein for allowing a vacuum conduit 160 to be influid communication with the interior of the patient interface 154. Theproximal tip 254 may optionally contain a microbarrier for inhibitingcontaminants from entering the patient interface 154 or being aspiratedthrough the vacuum conduit 160. Moreover, the rigid portion 250 maycarry a sample collection patch or other sample collector for collectingthe aspirated fluid sample as has been discussed. The rigid portion 250may be formed of a transparent, or semi-transparent, polymer such as,for example, polycarbonate or polypropylene to allow an operator tovisually verify the position of the device on a patient. The removablepatient interface 154 is removably connected to or otherwise fit withinand/or secured to the power head 100.

[0085] Thus, in accordance with the disposable patient interface aspectof the present invention, there is provided a disposable patientinterface for an intraductal fluid aspiration device. The interfacecomprises a sealing component and a vacuum chamber component. In theillustrated embodiment, the sealing component comprises a flexibletubular membrane, having a proximal end, a distal end and a passagewayextending therethrough. The proximal end has a smaller cross-sectionalarea than the distal end, defining a generally frustoconical structure.A rigid proximal cap is provided on the proximal end of the flexibletubular membrane, and contains the vacuum chamber. A vacuum port isprovided on the cap for connection to a source of vacuum.

[0086] The proximal cap 250 defines a chamber therein, and the capexhibits sufficient structural integrity that it resists collapse when avacuum of at least about 6 mm Hg is applied to the chamber. Preferably,the proximal cap 250 exhibits sufficient rigidity that it resistscollapse when a vacuum of at least about 100 mm Hg is applied to thechamber.

[0087] The unstressed diameter of the distal end of the flexible tubularmembrane 248 is generally within the range of from about 1 inches toabout 6 inches, although other sizes may be utilized depending upon thedesired clinical performance and intended patient population. Generally,the unstressed diameter of the distal end is no more than about 4inches. The diameter of the distal end may be stretched to at leastabout 150% of its unstressed diameter without rupturing the membrane.Preferably, the diameter of the distal end may be stretched to at leastabout 200%, and, in some embodiments, as much as 400% or more of itsunstressed diameter without rupturing the membrane.

[0088] In one application of the invention, the tubular member comprisesa styrene block copolymer, having a wall thickness of no more than about0.05 inches, and, in many embodiments, a wall thickness of no more thanabout 0.015 inches.

[0089] The axial length of the tubular membrane 248 from the distal endof the proximal cap to the distal end of the tubular membrane, along thesurface of the membrane, is generally within the range of from about 1inch to about 6 inches and, in many embodiments, within the range offrom about 2 inches to about 4 inches.

[0090] In one embodiment, the proximal cap 250 comprises at least afirst retention structure for releasable connection with a complementarysecond retention structure on the patient interface 154. The firstretention structure may comprise a recess on the proximal cap or aprojection on the proximal cap, and may be in the form of an annularbead or recess on the proximal tip 254.

[0091] In one embodiment, as shown in FIG. 5, the flexible portion 248is stretched to fit over the distal periphery of the petals 126, andsecured about a lip 190 formed on the outside surface of the petals. Thepatient interface 154 thus spans the gap between the individual petals126 and thereby provides a flexible biobarrier to inhibit patient tissuefrom being pinched between the adjustable petals 126. The rigid portion250 is removably mounted and snap fit or otherwise retained within thesecond concavity 166 as will be discussed in greater detail hereinafter.

[0092] Referring generally to FIGS. 5 and 6, an inflatable bladder 152conforms to the radially inwardly facing walls of at least the firstconcavity 164, and is sandwiched between the petals 126 and patientinterface 154. The inflatable bladder 152 is preferably configured toreceive an inflation media, thereby inflating and effectively reducingthe volume within at least the first concavity 164, thereby applying acompressive force to a breast positioned therein. The specifics of theinflatable bladder will be discussed in greater detail hereinafter.

[0093] Referencing FIG. 6, the power head 100 is shown from a rearisometric view. From this perspective, the control tubes 160, 162, and172 are illustrated. A vacuum conduit 160 is in communication with theinterior chamber in the patient interface 154. In the illustratedembodiment, the vacuum conduit 160 passes through a tube grommet 146 andis supported thereby. The tube grommet 146 provides bending support tothe vacuum conduit 160 and helps protect the tube from crimping orkinking. It further provides a fitting for receiving the distal tip 254of the rigid mounting portion 250 of the patient interface 154, as willbe shown and described hereinafter.

[0094] A pair of inflation conduits 162, 172, enter the power head 100and are in fluid communication with the inflatable bladder 152 therein.The inflation conduits 162, 172 may be configured to cooperate in avariety of ways. For example, both conduits may deliver and subsequentlywithdraw inflation media to the bladder; each conduit may serve anisolated inflation chamber within the bladder; or one inflation conduit162 may deliver inflation media, while the other conduit 172 maywithdraw inflation media. The inflation media may be any gas, liquid,gel, or other media suitable for inflating the inflatable bladder 152.In an embodiment in which a heat source is provided remotely from thepower head 100, the inflation media preferably also exhibits good heattransfer characteristics. Deionized water appears to have suitableperformance. The inflation conduits 162, 172, are preferably formed of amaterial capable of withstanding hoop stress such that the inflationpressure inflates the inflatable bladder 152 rather than expands theinflation conduits 162, 172.

[0095] A release ring 148 is provided to release the patient interfacefrom its mounted location and may optionally release the seal betweenthe patient interface 154 and the patient upon completion of theintraductal fluid aspiration procedure, and will be discussed in greaterdetail in reference to FIGS. 10a and 10 b. Alternatively, the vacuumrelease function may be assigned to the control unit.

[0096] Turning to FIG. 7, an exploded view of the power head componentsis shown. For ease in describing the interrelation between theconstituent components, they will be described in the context ofassembly. Many of the following described features become more readilyapparent in FIG. 8, and therefore, that figure is also referenced inrelation to the following description.

[0097] The main body 132 has a plurality of petal mounting flanges 124on its distal end, each having a threaded hole formed therein forreceiving a threaded fastener 130, and at least one face groove 174 forreceiving a portion of a petal 126. A plurality of petals 126 areprovided each having an integral mounting pin 176 configured to fitwithin the face groove 174 formed into each petal mounting flange 124. Aplurality of petal retainers 128 mount to the face of each petalmounting flange 124 to thereby secure the petal mounting pins 176 withinthe face grooves 174. In this manner, the petals 126 are hingedlymounted to the main body 132 and are pivotal about petal mounting pins176. However, other methods of pivotal or bondable connection, such asthrough a compliant mechanism, may be used as should be apparent tothose of ordinary skill in the art in light of the disclosure herein.This pivotal attachment allows for the power head 100 to besize-adjustable to fit different patients.

[0098] An adjustment ring 140 has a knurled portion 182 at a proximalend and an annular ridge 178 at a distal end. The knurled portion 182provides a non-tangential surface for gripping to ease in threading theadjustment ring 140 on the main body 132. The annular ridge 178cooperates with an annular groove 180, or equivalent structure, formedalong the inside diameter of the slide collar 134 to engage the twocomponents while inhibiting their disassembly. It is preferable that theadjustment ring 140 is free to easily rotate independent of the slidecollar 134 during adjustment, and for this reason, materials exhibitinga relatively low coefficient of friction are used. Polymers andelastomers such as polybutylene terephthalate (PBT), acrylonitrilebutadiene styrene (ABS), polyethylene, polypropylene, and polyurethaneare preferred because of their high strength to weight ratios, lowelectrical conductivity, and ability to receive lubricant and colorantadditives into their basic resins. Another benefit of using suchmaterials is that they can be processed from raw materials into a finalsize, shape, and finish through any one of several basic castingoperations, including injection molding, while maintaining the abilityto be machined through any standard chip-producing, material-removalprocess to create details not available through standard castingprocesses. Additional components, such as the petals 126, main body 132,and links 136 are also preferably fabricated of similar materials totake advantage of these properties.

[0099] The main body 132 has outer body threads 122 formed thereon forcooperating with internal threads 188 of the adjustment ring 140. Byrotating the adjustment ring 140 about the main body 132, the adjustmentring 140, and accompanying slide collar 134 are linearly translated. Themain body 122 has one or more longitudinal grooves 123 that cooperatewith corresponding tabs 133 inside the slide collar 134 to prevent theslide collar 134 from rotating about the main body 122. During assembly,the slide collar tabs 133 are inserted into the main body grooves 123such that the tabs track within the grooves 123 and prevent subsequentrotation of the slide collar 134 relative to the main body 122. Theslide collar 134 is coupled to mounting ribs 184 formed on the petals126 via pinned links 136. The mounting ribs 184 are spaced to flank thelink 136, and have a hole formed therethrough for receiving a pin 138.Likewise, the links 136 are hingedly attached to the slide collar 134 atmounting ribs 186. The pivotal mounting can be effected in any of anumber of ways, and is not limited to a pin 138 as shown.

[0100] As the adjustment ring 140 is threaded about the main body 132,the attached slide collar 134 translates linearly, which imparts alinear motion to the links 136 which, in turn, causes the petals 126 topivot about their attachment points. In this manner, the first concavity164 is adjustable throughout a range between an initial open position,and an adjusted, patient form-fitting, position. In one embodiment, thepetals are moveable between a fully open position, wherein the petalsare substantially co-planar to each other and perpendicular to thelongitudinal direction 168, and a fully closed position, wherein thepetals 126 come together and contact along their edges, extendinggenerally in parallel to the longitudinal axis. Thus, the minimum volumeencompassed by the petals 126 is constrained only by the specific petalgeometry. The petals 126 can be shaped such that the minimum volume ofthe first concavity 164 is substantially smaller than that achievable bythe illustrated petal design.

[0101] For example, FIG. 8 illustrates one embodiment of a petal designwherein each petal is identically sized and shaped. For example, eachpetal is about 2 in. wide in the transverse direction 170 by 1.75 in.high in the longitudinal direction 168, and is shaped such that it isconcave inwardly in both a longitudinal 168 and transverse 170direction. In this manner, the cooperating petals define a firstconcavity 164 that is substantially bowl or bell-shaped. The petals 126could be sized and shaped differently to provide a more individual fit.For example, the petals 126 could be shaped and/or arranged to provide asubstantially oval first concavity 164. Additionally, one or more petals126 may be fixedly attached, with the remainder adjustable, or one ormore petals 126 may exhibit different travel characteristics to resultin various form-fitting shapes. Four, or three or two (e.g. clam shellconfiguration) petals may also be used, depending upon the desiredmanufacturing cost and clinical performance.

[0102] It is the adjustability of the first concavity 164, defined bythe relative orientation of the plurality of petals 126 or otheradjustable support structure, that allows the device to be adjustable toallow a single device to accommodate a range of patient sizes, toprovide a comfortable fit and help create a seal between the power head100 and the patient in order to effectively carry out the aspirationprocedure.

[0103] The dimensions and adjustability range of the first concavity 164may be varied widely, as will be appreciated by those of skill in theart in view of the disclosure herein. In general, the distal openingdefined by the distal limit of the petals 126 has an adjustable diameterwithin the range of from about 2 inches to about 12 inches. Theadjustability is illustrated in reference to FIG. 13A and 13B whereinthe diameter “D” is adjustable within the range of from about 2 inches(D₁) to about 12 inches (D₂), and in certain embodiments, within therange of from about 3½ inches to about 6.5 inches. The second concavity166 has an inside diameter within the range of from about 1 inches toabout 4 inches. The first concavity 164 has an axial length within therange of from about 0 inches to about 12 inches, and, in manyembodiments, within the range of from about 0 inches to about 6 inches.The first concavity 164 has a generally conical, hemispherical or bellshaped contoured interior configuration, as previously described, aswill be appreciated by those of skill in the art.

[0104] Referring briefly to FIGS. 14A and 14B, when the device isadjusted to fit a patient, for example, the inside diameter of the firstcavity 164 is further movable between a first, large diameter D₃ whenthe bladder 152 is deflated and a second, reduced diameter D₄ when thebladder 152 is fully inflated. Diameters may be measured from ageometrical mid-point 233 on a first petal to a geometrical mid-point233 on a second, opposing petal, as a reference. The difference betweenD₃ and D₄ provides an indication of the fully inflated thickness in theradial direction of the opposing lobes 152 of the bladder. In manyembodiments of the present invention, the difference D₃−D₄ is within therange of from about 0.25 inches to about 2.5 inches. Generally, thedifference D₃−D₄ is within the range of from about ½ inch to about 1½inches. As will be appreciated by those of skill in the art, a D₃−D₄difference of 1 inch means that the patient contacting surface of eachopposing bladder lobe is movable throughout an operating range of about0.5 inches.

[0105] Returning to FIG. 8, and with supplemental reference to FIG. 7, atube support 144 is secured to the main body 132 by any suitable manner,such as threaded fasteners, and provides a support for the control tubes160, 162, 172 extending therethrough. Tube support 144 additionallycarries a tube grommet 146 which provides additional support to thevacuum conduit 160 as previously described. A release ring 148 isprovided to disengage the patient interface rigid portion 250 from itsmounted location. The release ring may optionally be used to release thevacuum seal between the patient interface 154 and patient. The purposeand operation of the release ring 148 and related components will bediscussed in greater detail in connection with FIGS. 10a and 10 b.

[0106] Referencing FIGS. 5 and 9, an inflatable bladder 152 isconfigured to fit at least within the first concavity 164. The main body132 includes indexing structures such as one or more mounting tabs 102(of FIG. 8) which position the inflatable bladder 152 toward the outercircumference of the main body 132. Furthermore, the inflation conduits162, 172 pass through holes formed in the main body (132 of FIG. 6) andexperience sliding friction therewith such that once the inflatablebladder 152 is positioned within the power head 100 and the inflationconduits 162, 172 are passed through the main body 132, the inflatablebladder 152 is inhibited from being dislodged from its desired positionby the resistance of the inflation conduits 162, 172 from being slidablydisplaced. The inflatable bladder 152 is in fluid communication withinflation conduits 162, 172, and in one embodiment, one conduit isconfigured to deliver inflation media while the other conduit isconfigured to return inflation media.

[0107] In one aspect, the inflatable bladder 152 is configured toinclude a plurality of lobes 204, each corresponding to a petal 126, andmay be optionally mounted thereto by adhesives, interference fitstructures or other effective mounting methods. The lobes 204 arepreferably generally rounded into a generally pear shape to allow thelobe to maintain a fairly uniform stress when under pressure. Each lobe204 in the illustrated embodiment is sized to contain between about 1 mLand 100 mL of inflation media, and more particularly, to contain betweenabout 5 mL and 20 mL. In one embodiment, the lobes 204 each have aninflated volume of about 10 ml, and have profile dimensions such thatwhen fully inflated they extend radially inwardly through a thickness ofabout 1.0 inches.

[0108] In general, when the lobes 204 are fully inflated, they protrudeinwardly between about 0.2 inches and about 2 inches from the inner wallof the petals 126, and in one embodiment, between about 0.75 inches andabout 1.5 inches. Aside from the first and last lobe, 206 and 208respectively, the outlet 210 of one lobe 204 connects to the inlet 212of an adjacent lobe 204. Although in the illustrated embodiment, aplurality of lobes 204 are connected sequentially in series, parallelflow paths or other configurations are possible as described herein.

[0109] The inflation conduit 162 is securely attached to the inlet 212of the first lobe 206 at 214 by any suitable manner, such as heatwelding, by adhesives, crimping, and the like, and delivers inflationmedia to the first lobe 206 at a predetermined flow rate. In oneembodiment, the inflatable bladder 152 is formed in a single die cut andheat welding step out of a material amenable to these techniques, suchas, for example, polyurethane film having a thickness between about0.003 inches and 0.030 inches. In one embodiment, a polyurethane filmthickness of 0.015 inches is preferred. The inflation conduits 162, 172may be permanently attached, such as by heat welding, during this singlefabrication step. The inflation media is allowed to flow through theremaining lobes 204 and out through the final lobe 208, which terminatesin a return conduit 172. The conduits 162, 172 may also be sealed to areservoir, discussed below, to provide the closed loop. The closed loopmay be charged with inflation media at the point of manufacture.

[0110] The return conduit 172 may have at least a portion that presentsa smaller diameter for the media to flow through, thereby creating anamount of back pressure in the fluid system. Any of a variety of flowrestrictors, such as apertures or reduced diameter flow paths may beused. In one embodiment, the return conduit 172 has a smaller insidediameter than the inflation conduit 162; however, the conduits 162, 172could share a common diameter and a fitting along the return conduit 172could include a portion having a diameter smaller than the inflationconduits 162, 172. In an alternative embodiment, a check valve may beplaced along the return flow path 172 thereby allowing an adjustablerestrictor for varying the back pressure which adjusts the inflationpressure. Additionally, an adjustable restrictor, such as a duck-billflap, will allow the return path flow to be varied, including blockingthe return flow path completely thereby causing a reverse inflationmedia flow to deflate the inflatable bladders 204 once the pump 262 isturned off. The flow restrictor may be located anywhere along the returnpath 172, including at the exit of the final bladder 208 or at the inletof the fluid reservoir 260. Alternatively, the return conduit 172 couldbe constricted by external forces to reduce the flow therethrough andincrease pressure in the upstream system. As a pump increases the flowof inflation media through the closed fluid system, the return line actsas a restrictor against which the pump creates pressure to inflate thelobes 204.

[0111] Thus, in accordance with the disposable fluid loop aspect of thepresent invention, there is provided a closed loop heating and/orcompression system for a nipple fluid aspiration device. The closed loopsystem comprises a plurality of inflatable bladders or lobes forproviding compression of a breast, a reservoir, and at least one fluidflow path for placing the bladders in fluid communication with thereservoir. As used herein, the bladder may be referred to either as amultiple lobed bladder, or a plurality of bladders in communication witheach other, and/or a common inflation source, without any intendeddistinction.

[0112] In the illustrated embodiment, the fluid flow path comprises amovable wall, such as a compressible tube or reservoir. This allowsforced circulation such as by exposing the tubing to a roller or platenpump, or by compressing the reservoir. The system generally comprises atleast about three inflatable bladders, and, in one embodiment, about sixinflatable bladders. Preferably, a heat exchange media, such as a fluidas has been described, is contained within the closed loop. Generally,each bladder has an inflated width of no more than about 3 inches and aninflated length of no more than about 4 inches. In many embodiments,each bladder has an inflated width of no more than about 2 inches and aninflated length of no more than about 3 inches.

[0113] The inflated thickness of each bladder may be varied widely,depending upon the desired performance characteristics. In general, eachbladder has an inflated thickness of no more than about 1 inch, whichprovides a 2 inch dynamic range for the inside diameter of theconcavity, during the compression and decompression cycles, as isdiscussed elsewhere herein.

[0114] A variety of modifications can be made to the disposable fluidloop, as will be apparent to those of skill in the art, in view of thestructural support aspect of the present invention. In general, theinflatable bladder disclosed herein is one manner of providing a patientinterface surface which is moveable between a first position in whichthe cavity has a relatively large cross sectional dimension and a secondposition in which the cavity has a relatively smaller cross sectionaldimension. The difference between the relatively large and relativelysmall cross sectional dimensions of the cavity is the working range ofthe compression system.

[0115] In an alternate embodiment, the support may be movable throughoutthe working range, to provide compression. In this embodiment, thesupport may be moveable through a larger moving range to provide a roughadjustment as has been described elsewhere herein. Once the roughadjustment has been achieved, the support is then moveable throughoutthe smaller compression working range, using any of a variety ofmechanical actuation devices such as a motor drive. In this embodiment,the inflatable bladder may be utilized to circulate a heating media, andnot be utilized to impart compression. Alternatively, the support may beprovided with an alternative heating mechanism such as an internalheating lumen for circulating a heated fluid, or internal electricalresistance coils or other heat source as will be appreciated by those ofskill in the art. In such an embodiment, the inflatable bladder may beentirely eliminated.

[0116] An operator of the illustrated intraductal fluid aspirationsystem can directly control the inflation pressure of the inflatablebladder 152 by varying the pump speed. The inflation pressure iscontrolled by the pump speed, due to the flow restriction imposed alongthe return conduit. The pump preferably has safety features built in tolimit its speed such that the inflation pressure provided by the pumpcannot exceed the burst strength of the inflatable bladder 152, which inone embodiment, is about 1000 mm Hg. Alternatively, limit valves may beprovided in communication with the inflation conduits 162, 172, as isknown in the art. The operating pressure within the inflatable bladdersduring the compression cycle preferably does not exceed about 1000 mmHg, and more preferably does not exceed about 420 mm Hg.

[0117] Referring back to FIG. 5, the inflatable bladder 152 creates acompression zone to facilitate intraductal fluid aspiration. Asdescribed, the inflatable bladder 152 is preferably in operativecommunication with an external inflation driver (not shown) through oneor more inflation conduits 162, 172. In one embodiment, the inflatablebladder 152 has a single inflation chamber and is operable between adeflated state and a fully inflated state in which the interior pressureof the inflation media reaches a constant pressure. In anotherembodiment, a plurality of discrete inflation chambers are providedwithin the inflatable bladder 152 and are selectively inflated to createvarious compression modes. In one embodiment, the compression modemimics a peristaltic motion such that tissue compression is accomplishedsequentially proximally. This may be accomplished by selectivelyinflating a plurality of inflation chambers in fluid communication witheach other, with each having a wall with a unique durometer orelasticity such that each inflation chamber inflates as a uniquethreshold inflation pressure is reached and/or exceeded. Alternatively,a plurality of inflation chambers may be interconnected in series byvalves that open at sequentially greater pressures thereby sequentiallyinflating the chambers as the inflation pressure increases.

[0118] By inflating the inflatable bladder 152, the volume within thefirst and second concavities 164, 166 is effectively reduced, therebyapplying a circumferential compressive force to a breast positionedtherein. The inflatable bladder 152 is configured such that thecompressive force is applied at a location that is anatomically adjacentor proximal to a patient's lactiferous sinus. Thus, the geometric centerof each lobe is generally positioned no more than about three inchesfrom the distal tip of the nipple. In this way, the intraductal fluid isencouraged to flow anatomically distally and is therefore expressed.

[0119] As discussed above, the inflation pump may be programmed to aparticular compression cycle characteristic, or may be adjustable by theclinician to optimize the aspiration function as desired. For example,compression cycles may be peristaltic, with a sequential compressionpattern from the patient's chest wall to an anatomically distal end.Alternatively, the compression cycle may be non peristaltic cycles, andmay be pulsatile within each cycle. In one embodiment, a roller pumpprovides pulsatile inflation of the inflatable bladder 152 at a pulserate between about 50 and 600 cycles per minute, which may add to thepatient's comfort during the procedure.

[0120] The inflation cycle may be sinusoidal having a period of betweenabout 1 and 20 cycles per minute. In one application of the invention,each compression cycle lasts about 10 seconds from empty to empty. A tensecond pulse with a sinusoidal wave form thus produces approximately 6inflation cycles per minute. Inflation cycles per minute may range fromabout one to about 20 or 30 cpm. In another embodiment, there may be asingle inflation cycle during the aspiration procedure in which theinflatable bladder 152 is inflated under pulsatile pressure throughoutthe procedure. It should be readily apparent to those of ordinary skillin the art that various inflation cycle modes could be substituted forthose described herein without departing from the scope of the claims.

[0121] In one embodiment, the inflation conduits 162, 172 are part of aclosed fluid loop which includes a fluid reservoir (260 of FIG. 12), afirst inflation conduit 162, the inflatable bladder 152, and a secondinflation conduit 172. In referring to a closed fluid loop, it is to beunderstood that the term “fluid” means any gas, liquid, or gel suitablefor use as inflation media. The same is true when referring to inflationfluid. The closed fluid system is thereby easily removed from the systemand replaced and may be disposed of as desired. Furthermore, a closedfluid system provides convenience in setup and operation of theintraductal fluid aspiration system in addition to patient and devicesafety by keeping the fluid confined.

[0122] Inflation media such as gas, liquid, or gel may be utilizeddepending upon the desired performance characteristics. In oneembodiment, a heat retaining gel such as morphing gel, available fromDow Coming, is utilized to enable the delivery of heat during thecompression cycle. In another embodiment, deionized water is used as theinflation media, which offers a low electrical conductivity and resistsalgae and bacteria growth.

[0123] In cooperation with the applied compression, a vacuum is createdby first forming a seal between the patient interface 154 and thepatient. Generally, the rigid portion 250 creates a concavity forreceiving a nipple and contacts the patient at a circumscribing locationthereto. An external vacuum generator, such as a pump (230 of FIG. 12),applies a negative pressure in the second concavity 166 through a vacuumconduit 160, which removes any trapped air within the concavities 164,166, thereby creating a vacuum therein and securely sealing at least therigid portion 250 to the patient. Vacuum may be applied constantlythroughout the pumping cycle, or may be pulsatile either in phase or outof phase with the compression cycles.

[0124] The pump 230 is generally capable of generating a vacuum withinan operating range of from 0 (pump off) to about 260 mm Hg. Althoughvacuum in excess of 260 mm Hg may also be utilized, vacuum in this areaor higher may cause rupture of microvasculature and is unnecessary toaccomplish the objectives of the present invention. For this reason,limit valves may be provided in communication with the vacuum conduit,as are known in the art, to limit the vacuum to no more than about 150mm Hg, or 200 mm Hg, or 250 mm Hg. Within the methods of the invention,negative pressures of 150-250 mm Hg are preferred, and these pressuresare maintained, for approximately 1-15 minutes, depending on thesensitivity of individual patients, oxytocin dosage and other factors.The pressure may be maintained constantly throughout the aspirationprocedure, or may be pulsatile.

[0125] Preferably, the power head 100 is provided with a heat source,such as a heated inflation media for inflating the inflatable bladder152. Alternatively, resistance heating elements may be provided in thepetals 126 and/or patient interface 154, powered by way of electricalconductors extending throughout the power head 100. In an embodimentwhere the patient interface 154 is filled with a heat retaining gel orother media for retaining heat, the patient interface 154 may be removedand heated such as in a microwave oven or other heat source prior touse. An ultrasound source may also be provided remotely or in the powerhead 100, for driving one or more ultrasound transducers in the powerhead 100 to assist in initial removal of keratin plugs that may occur atthe opening of the ducts, and possibly also to serve as a heatingsource.

[0126] Alternatively, the inflation media may be circulated through aheater 264, through a first inflation conduit 162 into the inflatablebladder 152, and back through a second inflation conduit 172 to maintainan elevated inflation fluid temperature within the inflatable bladder152. By circulating heated fluid through the closed loop the temperature(and inflation pressure) within the inflatable bladder 152 may beconveniently controlled. Preferably, temperatures in the range of about30° C. to about 55° C., and more preferably within the range of fromabout 37° C. to about 50° C., and in one embodiment, 45° C. aremaintained at the patient contact surface. There is a measurable heatloss as the heated inflation media travels through the inflationconduits 162, 172, and into the inflatable bladder 152, therefore, themedia is preferably heated to a temperature slightly higher thandesired. For example, a 46° C. temperature at the reservoir in oneembodiment of the invention produces a patient contact surfacetemperature of approximately 39.5°-40.5° C. It is believed that theapplied heat may lower the viscosity of the intraductal fluid inaddition to overcoming physiological patient resistance to aid in fluidaspiration.

[0127] Referring to FIGS. 10A and 10B, a release ring 148 is provided todisengage the patient interface rigid portion 250 from its mountedlocation. Additionally, the release ring 148 may optionally be used torelease the vacuum created within the second concavity 166 and therebybreak the seal between the patient and patient interface 154. Therelease ring 148 has a handle 218 having a bore therethrough forslideably mounting to a boss 184 of the tube support 144. The releasering 148 is preferably formed of cast polymer as previously describedherein. The release ring 148 has a shelf portion 220 for interactingwith a leaf spring 252 that is cantilevered to the tube support 144. Theleaf spring 252 contacts the shelf portion 220 and biases the releasering 148 in a distal direction. The release ring 148 further includes analignment flange 216 that fits into an alignment slot (not shown) formedin the main body 132 to ensure the proper mating of the constituentcomponents.

[0128] The tube support 144 and release ring 148 define an open spacefor receiving the rigid portion 250 of the patient interface 154. As thepatient interface 154 is mounted to the power head, the rigid portion250 is pushed into the cavity defined by the tube support 144 andrelease ring 148 until the distal tip 254 enters the vacuum cavity 194(of FIG. 8) formed in the tube grommet 146, and the rigid portion 250 isseated against the tube grommet 146 such that the malleable tube grommet146 compresses against the rigid portion 250 and forms an airtight sealtherewith.

[0129] The leaf spring 252 has a concave edge 256 for mating with thesubstantially cylindrical rigid portion 250 of the patient interface154. As the distal tip 254 is forced into the vacuum cavity 194, theconcave edge 256 of the leaf spring 252 contacts a portion along theouter periphery of the rigid portion 250. As the rigid portion 250slides past the leaf spring 252, the leaf spring 252 resiliently bendsin the direction of travel of the rigid portion 250, thus allowing therigid portion 250 to slide by without impeding the movement thereof.Once the rigid portion 250 is mounted, the leaf spring 252 impedes therigid portion 250 from dislodging from its mounted location. The concaveedge 256 of the leaf spring 252 impinges upon the periphery of the rigidportion 250 thereby constructively interfering with the undesiredwithdrawal of the rigid portion 250 from its mounted location. In thisway, the rigid portion 250 of the patient interface 154 is securelymounted thereby creating a substantially airtight seal with the vacuumcavity 194 of the tube grommet 146.

[0130] Upon completion of the procedure, the vacuum pressure is releasedto remove the power head 100 from the patient. This may be accomplishedby actuating the release ring 148. As the handle portion 218 of therelease ring 148 is manually actuated in a device proximal direction198, the release ring shelf 220 elastically deforms the leaf spring 252such that the patient interface rigid portion 250 is no longerconstrained in its mounted location. The patient interface flexibleportion 248, by virtue of being stretched to mount over the petals 126,is in tension, such that a releasing force is translated to the patientinterface rigid portion 250. As the leaf spring 252 is deformed suchthat it no longer contacts the outer periphery of the patient interfacerigid portion 250, the tension from the patient interface flexibleportion 248 causes the distal tip 254 of the rigid portion 250 towithdraw from the vacuum cavity 194 thereby breaking the vacuum seal andallowing the power head 100 to be removed from a patient.

[0131] Alternatively, the vacuum pressure may be released by a controlunit microprocessor protocol. For example, the external vacuum pump (notshown) may be configured with a release valve that is selectivelyoperable to interrupt the vacuum. As another alternative, the vacuumpump may be reversible, thereby creating a positive pressure within thesecond concavity 166 further easing the disconnection with the patient.In another embodiment, a valve may be present along the vacuum conduit160, or within the first or second concavities 164, 166, for releasingthe vacuum. It will be apparent to one of skill in the art that thereare a variety of ways to break the vacuum seal that are not disclosedherein yet are contemplated as being within the scope hereof.

[0132] Referring to FIG. 12, a self-contained intraductal fluidaspiration device is depicted schematically illustrating the components.It should be apparent to one of skill in the art that the device may bea desk top unit, or alternatively stored on a movable cart, such thatone device can be selectively utilized at various patient treatmentlocations. Although disclosed with only a single power head 100 forsimplicity, the system may be provided with two power heads 100 forsimultaneous operation. A control unit 200 houses the apparatuses fordelivering heat, inflation media, and vacuum pressure, in addition tohousing feedback and control devices 266 to allow an operator thereof tocustomize the operational characteristics, such as, for example,temperature, inflation pressure, inflation cycle characteristics, vacuumpressure, vacuum cycle characteristics, and the like. The control unit200 houses a vacuum generator pump 230 for creating a vacuum pressurewithin at least the second concavity 166 of the power head 100 aspreviously described. The vacuum conduit 160 may be permanently attachedto the power head 100, the vacuum generator pump 230, or may beremovably attached to both. In this way, the vacuum conduit 160 may bereplaced as desired.

[0133] The control unit 200 further contains a pump 262 for driving thecompression cycle, and in one embodiment, the pump is a three orfour-roller peristaltic pump. The pump 262 is preferably controlled by acontrol circuit, which includes instructions for controlling the pump262 to deliver various modes of operation as described herein. Thecontrol circuit can also include instructions for operating the vacuumgenerating pump 230, and is configured to control the vacuum pressurescreated by the vacuum generating pump 230. The pump 262 is incompressive contact with at least a portion of one of the inflationconduits 162, and imparts a peristaltic pumping action thereto to forceinflation media to flow through the inflation conduit 162. The pump 262may also be reversible to deflate the inflatable bladders 204.

[0134] The inflation conduits 162, 172, meet at one end in a fluidreservoir 260 that contains a volume of inflation media. The fluidreservoir 260 may be a rigid tank, or may be a flexible bag, and maycontain a volume within the range of from about 50 mL to one liter, andin some embodiments, may contain between about 150 mL and 300 mL, and inone embodiment, approximately 200 mL. The fluid reservoir 260 isadjacent to, and removably in thermal contact with, a heat exchanger 264for conducting thermal energy into the inflation media. The heatexchanger 264 may be any of a number of known heaters, such as, forexample, an electrical resistance heater. As described above, theinflation media is heated to a temperature within the range of about 30°C. to about 55° C., and more preferably within the range of from about37° C. to about 50° C. To reduce the warm up time prior to use, asecondary, or even a tertiary heater may be installed.

[0135] The heated inflation media flows through an inflation conduit172, and into the inflatable bladder 152 within the power head 100. Theinflation media may be continuously cycled through the power head 100and back to the fluid reservoir 260 for heating.

[0136] The inflation conduits 162, 172, inflatable bladder 152, andfluid reservoir 260 form a closed fluid loop, which is preferablyremovable from the system for periodic replacement. To install the fluidloop, the fluid reservoir 260 is inserted into a compartment housed inthe control unit 200, and one of the inflation conduits 162, 172, ispositioned across the pump 262. In this way, the closed fluid loop isisolated from the rest of the system and may easily be replaced, ifnecessary. It also keeps the inflation media separate from anyelectronics that are moisture sensitive. Hence, the closed fluid loop isnot only convenient, but adds an element of safety to the apparatus, theoperator, and the patient. To further protect the sensitive componentsin the control unit 200, bulkheads within the control unit 200 keep theelectronics separate from the fluid loop.

[0137] Thus, according to one aspect of the present invention, a controlunit contains circuitry and hardware for effecting the treatment methodsdisclosed herein. Specifically, a vacuum generator pump, fluidcirculation pump, heat exchanger, and concomitant drivers are providedfor carrying out an intraductal fluid aspiration procedure.

[0138] Some embodiments disclosed herein teach the use of a samplecollector or reservoir positioned in fluid communication with thepatient interface 154 to allow collection of intraductal fluid. In otherembodiments, the aspirated fluid is allowed to collect on the tissuecontacting surface 156 of the patient interface 154, with an amount ofaspirated fluid likely to remain on the patient's skin, for subsequentcotton swab collection.

[0139] Additional embodiments may include a fluid detection device foralerting the operator when a fluid sample has been aspirated. Thedetection device may be in the form of a conductivity sensor in whichthe aspirated fluid bridges an electrical gap and completes anelectrical circuit for actuating a visual or audible cue to alert anoperator that a fluid sample has been collected. Alternatively, thefluid detection device may comprise a pH strip that will change color orotherwise alert an operator that a fluid sample has been collected.

[0140] To perform an intraductal fluid aspiration procedure, atechnician prepares the patient by applying alcohol to remove keratinplugs. The technician determines the approximate size of breast to betested, either visually, or through patient disclosure. The power head,with attached patient interface, may be rough adjusted to conform to thesize and/or shape of the breast to be tested. Alternatively, the powerhead is fully opened to facilitate proper positioning around the nipple.Subsequent to contacting the patient, the power head is adjusted toproperly fit the patient undergoing testing. Preferably, prior tocontacting the patient, the inflation media has been preheated to adesired temperature and the pump idly delivers media flow through thepower head. Once the power head is in contact with the patient and hasbeen properly adjusted, the inflatable bladders receive additionalinflation media and begin compressing the breast. A vacuum may beapplied to at least the nipple to encourage fluid aspiration.

[0141] The procedure is anticipated to take approximately between 3 and20 minutes to complete, and more preferably, is anticipated to take nomore than approximately 10 minutes to complete. The procedure iscomplete upon either (1) collecting a sufficient volume of intraductalfluid, or (2) timing out of the procedure and determining that asufficient fluid sample cannot be collected during this initiation ofthe procedure.

[0142] Upon procedure completion, the compression is halted and theinflatable bladder is deflated. Additionally, the vacuum is ceased and avacuum releasing mechanism is actuated to remove the power head from thepatient. In one embodiment where no sample collection patch is used, thefluid sample will collect on the inner surface of the patient interface,with a volume of fluid likely remaining on the patient for cotton swabcollection. In the alternative, a fluid collection patch may be insertedinto the patient interface such that it maintains contact with thenipple and collects the fluid sample by absorption.

[0143] Although the present inventors believe that sufficient samplevolume will be obtainable from most patients using the heat, compressionand suction cycles provided by the pump disclosed herein, some patientsmay benefit from administration of one or more agents to enhanceproductivity. For example, oxytocin may be administered, preferably viaintranasal administration, in amounts effective to stimulate mammaryfluid expression in the patient. Once a sufficient post-administrationtime period has elapsed to allow the oxytocin to reach and stimulatetarget alveolar-ductal tissues, the breast is pumped and a biologicalsample is collected, as described above. After the sample is collected,a bioassay is conducted on the sample to determine the presence and/oramount of a selected breast disease marker, preferably a breast cancermarker or panel of breast cancer markers, in the sample.

[0144] One additional manner of increasing the collected fluid volume isto introduce a carrier fluid retrograde into the duct, such as throughthe use of a pressurized stream directed to the external opening of theduct. The carrier may alternatively be introduced using an introductionneedle or cannula which is advanced either transluminally through theduct or percutaneously. The carrier fluid may increase mobilization ofcellular fragments and other markers, which will be available uponaspiration of the fluid for assay. Aspiration may occur eitherimmediately following introduction of the carrier fluid, or after asufficient indwelling period of time to permit mobilization of carriersoluble or carrier transportable cells, cell components, or markers.

[0145] Any of a wide variety of carriers may be utilized, depending uponthe desired clinical objective. For example, an aqueous solution may beprovided with any of a variety of drugs or other active agents to eithertreat the breast, or facilitate the release and/or transport ofidentifiable markers.

[0146] Thus, there is provided in accordance with the present inventiona method of screening for breast cancer or other breast disease,comprising the steps of providing a patient having at least one breastduct with an external opening. A stream of carrier fluid is directedunder pressure into the opening to introduce a volume of carrier fluidinto the duct. The fluid is thereafter removed from the duct through theexternal opening, and the removed carrier fluid is screened for at leastone indicium of a physiological condition such as a marker as discussedin greater detail elsewhere herein. The removing carrier fluid step ispreferably accomplished by the application of suction to the externalopening of the duct. Preferably, suction is accompanied by compressionsuch as peristaltic or other systemic compression. The compressiondevice is preferably heated, such as in accordance with the devicediscussed above. The screening step may be accomplished by screening forcytologically abnormal cells, or markers as discussed in detailelsewhere herein.

[0147] Another aspect of the method includes the introduction of atherapeutic species into a breast duct, with or without subsequentaspiration for marker assay. In accordance with this method, a media isprovided, comprising a carrier and at least one therapeutic species. Astream of a media is directed at the external opening to the duct, tointroduce media into the duct.

[0148] Any of a variety of devices may be utilized, to direct apressurized fluid stream. See, for example, U.S. Pat. No. 5,399,163 toPeterson, et al., entitled “Needleless Hypodermic Injection Methods andDevice,” the disclosure of which is incorporated in its entirety hereinby reference. Such devices are currently known in the arts of needlelessinjection and surgical pressurized water cutting devices, both of whichmay be modified to reduce the velocity of the fluid stream so that it isinsufficient to cause tissue damage but sufficient to introduce carrierfluid retrograde into the duct. Introduction may be further facilitatedby optimizing the viscosity and temperature of the fluid carrier, whichmay be accomplished through routine experimentation by those of ordinaryskill in the art in view of the disclosure herein. Powered carrierintroduction is preferably preceded by keratin plug removal, asdiscussed elsewhere herein.

[0149] As used herein, the term breast disease marker refers to anycell, cell fragment, protein, peptide, glycoprotein, lipid, glycolipid,proteolipid, or other molecular or biological material that is uniquelyexpressed (e.g. as a cell surface or secreted protein) by diseasedbreast cells, or is expressed at a statistically significant, measurablyincreased or decreased level by diseased breast cells, or in associationwith breast disease (e.g. a protein expressed by an infectious agentassociated with breast disease), or is expressed at a statisticallysignificant, measurably increased or decreased level by diseased breastcells compared to normal breast cells, or which is expressed bynon-diseased breast cells in association with breast disease (e.g. inresponse to the presence of diseased breast cells or substances producedtherefrom). Breast disease markers can also include specific DNA or RNAsequences marking a deleterious genetic change, or an alteration inpatterns or levels of gene expression significantly associated withbreast disease. Preferred breast disease markers include markers ofbreast infections, benign neoplasia, malignant neoplasia, pre-cancerousconditions, and conditions associated with an increased risk of cancer.Breast disease markers include breast cancer markers.

[0150] As used herein, the term breast cancer marker refers to a subsetof breast disease markers, namely any protein, peptide, glycoprotein,lipid, glycolipid, proteolipid, or other molecular or biologicalmaterial that is uniquely expressed (e.g. as a cell surface or secretedprotein) by cancerous cells, or is expressed at a statisticallysignificant, measurably increased or decreased level by cancerous cellscompared to normal cells, or which is expressed by non-cancerous cellsin association with cancer (e.g. in response to the presence ofcancerous cells or substances produced therefrom). Breast cancer markerscan also include specific DNA or RNA sequences marking a deleteriousgenetic change, or an alteration in patterns or levels of geneexpression significantly associated with cancer. In addition, breastcancer markers can include cytological features of whole cells presentin mammary fluid, such as nuclear inclusions or cytoplasmic structuresor staining attributes uniquely expressed by, or associated with,cancerous cells.

[0151] Among the breast cancer markers that are useful within themethods of the invention, a subset are described in representativereview articles by Porter-Jordan et al., Hematol. Oncol. Clin. NorthAmer. 8: 73-100, 1994; and Greiner, Pharmaceutical Tech, May, 1993, pp.28-44, each incorporated herein by reference in its entirety. Othersuitable markers are also widely known and can be readily incorporatedinto the methods of the invention using information and methodsgenerally known or available in the literature. Preferred breast cancermarkers for use within the invention include well characterized markersthat have been shown to have important value for determining prognosticand/or treatment-related variables in human female patients. As notedpreviously, prognostic variables are those variables that serve topredict outcome of disease, such as the likelihood or timing of relapseor survival. Treatment-related variables predict the likelihood ofsuccess or failure of a given therapeutic program. Determining thepresence or level of expression or activity of one or more of thesemarkers can aid in the differential diagnosis of patients with malignantand benign abnormalities, and can be useful for predicting the risk offuture relapse or the likelihood of response to a selected therapeuticoption.

[0152] It is important to note, however, that the invention does notrely solely on breast disease markers that meet the stringentrequirements of sensitivity and specificity that would render the markerimmediately acceptable for clinical application to human patients. Onthe contrary, a number of breast disease markers contemplated within theinvention fall short of these stringent criteria, and nonethelessprovide useful information that can be of substantial benefit indetecting, differentially diagnosing or managing breast health includingbreast cancer. Such non-clinically accepted markers are useful forimmediate application within the methods of the invention as basicresearch tools, and as adjunctive tools in clinical applications. Beyondthese immediate applications, many such markers are expected to befurther developed and refined according to the methods of the inventionto the point of direct clinical applicability, particularly in assaymethods that analyze combinations of markers to generate complementarydata of greater predictive value than data yielded by individual markersalone.

[0153] The preferred assay methods of the invention particularly focuson breast cancer markers associated with tumorigenesis, tumor growth,neovascularization and cancer invasion, and which by virtue of thisassociation provide important information concerning the risk, presence,status or future behavior of cancer in a patient. As noted previously,tumorigenesis and tumor growth can be assessed using a variety of cellproliferation markers (for example Ki67, cyclin D1 and PCNA). Tumorgrowth can also be evaluated using a variety of growth factor andhormone markers (for example estrogen, EGF, erbB-2, and TGF.alpha.),receptors of autocrine or exocrine growth factors and hormones (forexample IGF and EGF receptors), or angiogenic factors. In addition totumorigenic, proliferation and growth markers, a number of markersprovide information concerning cancer invasion or metastatic potentialin cancer cells, for example by indicating changes in the expression oractivity of cell adhesion or motility factors. Exemplary markers in thiscontext include Cathepsin D, plasminogen activators and collagenases. Inaddition, expression levels of several putative tumor “suppressor”genes, including nm23, p53 and rb, provide important data concerningmetastatic potential, or growth regulation of cancer cells. Assaysdirected to divalent cations, such as Ca²⁺, Zn²⁺, and the like may alsobe helpful in providing important information concerning the risk,presence, status or future behavior of breast cancer. A large number andvariety of suitable breast cancer markers in each of these classes havebeen identified, and many of these have been shown to have importantvalue for determining prognostic and/or treatment-related variablesrelating to breast cancer.

[0154] Depending upon the chemistry of any particular assay, the resultsmay be processed and expressed in a variety of ways. For example, forcertain assays, a color change may be expressed directly from the samplecollection patch in the pump. For other assays, the sample collectionpatch may be removed from the pump and developed in a desk topdeveloping kit which includes whatever reagents, rinse solutions orother materials may be necessary to produce a result. For other assays,the sample collection patch is mailed or otherwise transported to asuitable laboratory for processing.

[0155] Prior to or concurrent with each assay run of the invention,particularly in the case of assays preformed at a remote laboratory, apreliminary evaluation may be performed to verify sample origin and/orquality. The focus of such preliminary evaluations is to verify that thesample collected in the collection patch is indeed of mammary origin,and is not contaminated with other potential contaminants, such as sweatfrom skin surrounding the nipple. For these sample verificationpurposes, a variety of assays are available which identify mammary fluidmarkers known to be present in mammalian mammary fluid, and which arepreferably highly specific markers for mammary fluid (i.e. markers whichare typically always present in mammary fluid and which are absent fromall, or most of, other potentially contaminating bodily fluids andtissues).

[0156] However, an acceptable level of specificity for mammary fluidmarkers within the methods of the invention is provided by markers thatare simply known to be present in mammary fluid, even though they may bepresent in other bodily fluids. One such marker is the enzyme lysozyme,which is a normal component of human serum, urine, saliva, tears, nasalsecretions, vaginal secretions, seminal fluid, and mammary fluid.Lysozyme (muramidase) is an enzyme which hydrolyzes beta 1,4-glycosidiclinkages in the mucopolysaccharide cell wall of a variety ofmicroorganisms resulting in cell lysis. Quantitative measurement oflysozyme is readily accomplished by a well known agar plate diffusionmethod, described in detail in the instructions provided with theQuantiplate.RTM. lysozyme test kit, available from Kallestad, SanofiDiagnostics (Chasta, Minn.), incorporated herein by reference in itsentirety.

[0157] Other mammary fluid markers for sample verification that are morespecific than lysozyme are preferred within the methods of theinvention, and can be readily incorporated within the invention based onpublished and generally known information. The most preferred amongthese markers are proteins and other biological substances that arespecifically expressed or enriched in mammary fluid. A diverse array ofsuitable markers in this context have been characterized and havealready been used to develop specific antibodies, including affinitypurified and monoclonal antibodies. These antibodies can in turn beemployed as immunological probes to determine the presence or absence,and/or to quantify, selected mammary fluid markers to verify mammaryfluid sample origin and quality.

[0158] Mammary fluid markers of particular interest for use within theinvention include specific cytokeratins that are characteristicallyexpressed by normal and cancerous mammary epithelial cells, againstwhich specific panels of antibody probes have already been developed.(See for example, Nagle, J. Histochem. Cytochem. 34: 869-881, 1986,incorporated herein by reference in its entirety). Also useful asmammary fluid markers are the human mammary epithelial antigens(HME-Ags) corresponding to glycoprotein components of the human milk fatglobulin (HMFG) protein, against which specific antibodies (e.g. antiHMFG1, Unipath, U.K.) are also available. (see Rosner et al., CancerInvest. 13: 573-582, 1995; Ceriani et al. Proc. Natl. Acad. Sci. USA 74:582-586, 1982; Ceriani et al., Breast Cancer Res. Treat. 15; 161-174,1990, each incorporated herein by reference in its entirety).

[0159] To conduct the breast disease marker assays provided within theinvention, a collected biological sample from mammary fluid is generallyexposed to a probe that specifically binds to a selected breast diseaseor breast cancer marker, or otherwise interacts with the marker in adetectable manner to indicate the presence or absence, or amount, of thebreast disease or breast cancer marker in the sample. Selected probesfor this purpose will generally depend on the characteristics of thebreast disease marker, i.e. on whether the marker is a proteinpolynucleotide or other substance. In preferred embodiments of theinvention, the breast disease marker is a protein, peptide orglycoprotein, all of which are effectively targeted in breast diseasemarker assays using specific immunological probes. These immunologicalprobes can be labeled with a covalently bound label to provide a signalfor detecting the probe, or can be indirectly labeled, for example by alabeled secondary antibody that binds the immunological probe to providea detectable signal.

[0160] General methods for the production of non-human antisera ormonoclonal antibodies (e.g., murine, lagormorpha, porcine, equine) arewell known and may be accomplished by, for example, immunizing an animalwith a selected breast disease marker protein, peptides synthesized toinclude part of the marker protein sequence, degradation productsincluding part of the marker protein sequence, or fusion proteinsincluding all or part of the marker protein linked to a heterologousprotein or peptide. Within various embodiments, monoclonal antibodyproducing cells are obtained from immunized animals, immortalized andscreened, or screened first for the production of an antibody that bindsto the selected breast cancer marker protein or peptide, and thenimmortalized.

[0161] It may be desirable to transfer the antigen binding regions(i.e., F(ab′)2 or hypervariable regions) of non-human antibodies intothe framework of a human antibody by recombinant DNA techniques toproduce a substantially human molecule. Methods for producing such“humanized” molecules are generally well known and described in, forexample, U.S. Pat. No. 4,816,397 (incorporated herein by reference inits entirety). Alternatively, a human monoclonal antibody or portionsthereof may be identified by first screening a human B-cell cDNA libraryfor DNA molecules that encode antibodies that specifically bind to theselected breast disease marker according to the method generally setforth by Huse et al. (Science 246: 1275-1281, 1989 (incorporated hereinby reference in its entirety). The DNA molecule may then be cloned andamplified to obtain sequences that encode the antibody (or bindingdomain) of the desired specificity.

[0162] Also contemplated within the invention are bifunctionalantibodies having independent antigen binding sites on eachimmunoglobulin molecule (as disclosed for example in Thromb. Res. Suppl.X: 83, 1990, and in The Second Annual IBC International Conference onAntibody Engineering, A. George ed., Dec. 16-18, 1991; each incorporatedherein by reference in its entirety), as well as panels of individualantibodies having differing specificities. Bifunctional antibodies andantibody panels of particular use within the invention includeantibodies and panels of antibodies that bind to two or more selectedbreast disease markers to generate complementary data of greaterpredictive value than data yielded by individual markers alone.

[0163] Monoclonal antibodies are particularly useful within theinvention as labeled probes to detect, image and/or quantify thepresence or activity of selected breast disease markers. In thiscontext, monoclonal antibodies that specifically bind to selected breastdisease markers are provided which incorporate one or more well knownlabels, such as a dye, fluorescent tag or radiolabel. By incorporatingsuch a label, the antibodies can be employed in routine assays todetermine expression, localization and/or activity of one or moreselected breast disease markers in a biological sample including, orderived from, mammary fluid.

[0164] Results of these assays to determine expression, localizationand/or activity of a selected breast disease marker in a test sampletaken from a patient at risk for breast disease, or known to have breastdisease, can be compared to results from control studies detectingand/or quantifying the same marker in biological samples obtained fromnormal patients negative for breast disease. In this manner, baselinedata and cutoff values can be determined according to routine methods torefine the assays of the invention and adapt them for direct clinicalapplication.

[0165] Detection and/or quantification of breast disease markers in thebiological samples of the invention can be accomplished using a varietyof methods. Preferred methods in this regard include well known ELISAimmunoassays, immunoprecipitation assays, and various solid phaseimmunoassays including Western blotting, dot blotting and affinitypurification immunoassays, among other methods. Comparable methods aredisclosed herein, or are elsewhere disclosed and known in the art, forusing non-antibody probes to detect and/or quantify the expressionand/or activity of breast disease markers. Suitable non-antibody probesfor use within the invention include, for example, labeled nucleotideprobes that hybridize at standard or high stringency to DNA transcriptsof oncogenes and other DNA sequences associated with elevated breastdisease risk, or with mRNA transcripts encoding breast disease markerproteins. Other suitable probes include labeled ligands, bindingpartners and co-factors of breast disease markers (e.g. growth factorreceptor ligands, or substrates of breast cancer associated proteasessuch as Cathepsin D).

[0166] In certain embodiments of the invention, cDNA and oligonucleotideprobes are employed in Northern, Southern and dot-blot assays foridentifying and quantifying the level of expression of a selected breastdisease marker in cell samples collected from expressed mammary fluid.Measuring the level of expression of breast disease markers according tothese methods will provide important prognostic and treatment-relatedinformation for assessing a broad range of breast disease, including thegenesis, growth and invasiveness of cancer, in mammals, particularlyhumans. For example, assays utilizing oligonucleotide probes will assistearly screening to evaluate heritable genetic lesions associated withbreast cancer, and to distinguish between pre-cancerous, early cancerousand likely metastatic lesions in patients.

[0167] In addition to the above mentioned sample extraction, collectionand assay methods, the invention also provides kits and multicontainerunits comprising reagents and components for practicing the samplecollection and assay methods of the invention. Briefly, these kitsinclude basic components for obtaining a biological sample from mammaryfluid.

[0168] A pharmaceutical preparation of oxytocin in a biologicallysuitable carrier may optionally be included. Preferably, the oxytocinpreparation is provided in an intranasal spray applicator and containsapproximately 40 USP units of oxytocin per ml of liquid carrier, whichcarrier is a simple, inexpensive buffered saline solution. Preferredapplicators can be in any of a variety of pressurized aerosol orhand-pump reservoir forms, with a nozzle for directing a liquid spray ofthe oxytocin into a patient's nostril.

[0169] The breast pump of the present invention is also provided. Thepump is designed to generate intermittent or sustained negativepressures in an area surrounding the nipple of between about 50-200mmHg, as well as heat and compression as has been discussed. Preferably,the breast pump serves a dual purpose of facilitating mammary fluidexpression from the nipple, and to provide the reservoir or solid phasecollecting device incorporated within the breast pump for biologicalsample collection.

[0170] Kits for practicing the assay methods of the invention include asuitable container or patch or other device for collecting a biologicalsample from expressed mammary fluid. A range of suitable collectiondevices are contemplated corresponding to a wide range of suitablebiological samples that may be collected from the expressed mammaryfluid. For example, simple sterile containers or reservoirs are providedto collect whole mammary fluid. Alternatively, a variety of solid phasedevices, including glass or plastic slides, membranes, filters, beadsand like media, are provided to receive or partition selected liquid orsolid fractions of the mammary fluid, to receive or partition cells orcellular constituents from the mammary fluid, or to receive or partitionpurified or bulk proteins, glycoproteins, peptides, nucleotides(including DNA and RNA polynucleotides) or other like biochemical andmolecular constituents from the mammary fluid. A wide variety of suchsample collection devices can be readily adapted for use within specificembodiments of the invention. These collection devices may be providedas a component of the breast pump (such as a removable fluid reservoiror nitrocellulose filter placed within the pump to directly receive orcontact the expressed mammary fluid as it is pumped), or may be providedseparately (for example as a non-integral membrane, filter, affinitycolumn or blotting material to which mammary fluid or mammary fluidcomponents are exposed to collect a biological sample for assaypurposes).

[0171] Although the foregoing invention has been described in terms ofcertain preferred embodiments, other embodiments and applications willbecome apparent to those of ordinary skill in the art in view of thedisclosure herein. Accordingly, the present invention is not intended tobe limited by the recitation of preferred embodiments, but is intendedto be defined solely by reference to the appended claims.

What is claimed is:
 1. A disposable patient interface for an intraductalfluid aspiration device, comprising: a flexible tubular membrane, havinga proximal end, a distal end and a passageway extending therethrough,wherein the proximal end has a smaller cross sectional area than thedistal end; a rigid proximal cap on the proximal end of the flexibletubular membrane; and a vacuum port on the cap for connection to asource of vacuum.
 2. A disposable patient interface as in claim 1,wherein the unstressed diameter of the distal end is within the range offrom about 2 inches to about 4 inches.
 3. A disposable patient interfaceas in claim 1, wherein the unstressed diameter of the distal end is nomore than about 4 inches.
 4. A disposable patient interface as in claim1, wherein the diameter of the distal end may be stretched to at least150% of its unstressed diameter without rupturing the membrane.
 5. Adisposable patient interface as in claim 1, wherein the diameter of thedistal end may be stretched to at least 200% of its unstressed diameterwithout rupturing the membrane.
 6. A disposable patient interface as inclaim 1, wherein the axial length of the tubular membrane from thedistal end of the proximal cap to the distal end of the tubularmembrane, along the surface of the membrane, is within the range of fromabout 1 inch to about 6 inches.
 7. A disposable patient interface as inclaim 1, wherein the axial length of the tubular membrane from thedistal end of the proximal cap to the distal end of the tubularmembrane, along the surface of the membrane, is within the range of fromabout 2 inches to about 4 inches.
 8. A disposable patient interface asin claim 1, wherein the proximal cap defines a chamber therein.
 9. Adisposable patient interface as in claim 1, wherein the proximal capexhibits sufficient rigidity that it resists collapse when a vacuum ofat least about 150 mm Hg is applied to the chamber.
 10. A disposablepatient interface as in claim 9, wherein the proximal cap exhibitssufficient rigidity that it resists collapse when a vacuum of at leastabout 250 mm Hg is applied to the chamber.
 11. A disposable patientinterface as in claim 1, wherein the proximal cap comprises at least afirst retention structure for releasable connection with a complementarysecond retention structure on a handpiece.
 12. A disposable patientinterface as in claim 1, wherein the retention structure comprises arecess on the proximal cap.
 13. A disposable patient interface as inclaim 1, wherein the retention structure comprises a projection on theproximal cap.
 14. A disposable patient interface as in claim 1, whereinthe tubular membrane comprises a styrene block copolymer.
 15. Adisposable patient interface as in claim 1, wherein the tubular membranehas a wall thickness of no more than about 0.25 inches.
 16. A disposablepatient interface as in claim 1, wherein the tubular membrane has a wallthickness of no more than about 0.125 inches.
 17. A method of making adisposable patient interface for an intraductal fluid aspiration device,comprising the steps of: molding a proximal cap; and overmolding aflexible tubular membrane.